Delivery of Human Mesenchymal Adipose-Derived Stem Cells Restores Multiple Urological Dysfunctions in a Rat Model Mimicking Radical Prostatectomy Damages Through Tissue-Specific Paracrine Mechanisms
Delivery of Human Mesenchymal Adipose-Derived Stem Cells Restores Multiple Urological Dysfunctions in a Rat Model Mimicking Radical Prostatectomy Damages Through Tissue-Specific Paracrine Mechanisms
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DOI：
10.1002/stem.2226
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发表时间：
2016-02-01
期刊：
影响因子：
5.2
通讯作者：
Rodriguez, Anne-Marie
中科院分区：
文献类型：
--
作者：
Yiou, Rene;Mahrouf-Yorgov, Meriem;Rodriguez, Anne-Marie
尿失禁(UI)和勃起功能障碍(ED)是最常见的功能性泌尿系统疾病，也是前列腺癌根治性前列腺切除术(RP)的主要后遗症。间充质干细胞(MSC)治疗有望修复RP引起的组织损伤。由于缺乏准确复制RP术后临床UI和ED的动物研究，对MSC在这种环境下的泌尿系统益处的潜在机制知之甚少。为了确定MSC是否以及通过何种机制可以修复同一动物的横纹尿道括约肌(SUS)和阴茎的损伤，我们将人多潜能脂肪干细胞作为MSC模型，在复制RP后UI和ED的免疫活性大鼠模型中进行移植。在这个模型中，我们在同一动物的RP损伤后第7天到第90天使用非侵入性方法证明，在SUS和阴茎中同时应用MSC显著改善了尿控和勃起功能。MSC治疗的再生效果不是由于注射部位的转分化和牢固的植入所致。相反，我们的结果表明，MSC在两个靶器官中的益处可能涉及旁分泌过程，不仅通过MSC释放可溶性因子，而且还激活受体的分泌体。MSC的这两种作用因靶组织和受损细胞类型的不同而不同。总之，我们的工作为MSC的再生特性提供了新的见解，并支持MSC从单一来源修复多种类型的损伤的能力，例如在同一个体中看到的RP后的损伤。
Urinary incontinence (UI) and erectile dysfunction (ED) are the most common functional urological disorders and the main sequels of radical prostatectomy (RP) for prostate cancer. Mesenchymal stem cell (MSC) therapy holds promise for repairing tissue damage due to RP. Because animal studies accurately replicating post-RP clinical UI and ED are lacking, little is known about the mechanisms underlying the urological benefits of MSC in this setting. To determine whether and by which mechanisms MSC can repair damages to both striated urethral sphincter (SUS) and penis in the same animal, we delivered human multipotent adipose stem cells, used as MSC model, in an immunocompetent rat model replicating post-RP UI and ED. In this model, we demonstrated by using noninvasive methods in the same animal from day 7 to day 90 post-RP injury that MSC administration into both the SUS and the penis significantly improved urinary continence and erectile function. The regenerative effects of MSC therapy were not due to transdifferentiation and robust engraftment at injection sites. Rather, our results suggest that MSC benefits in both target organs may involve a paracrine process with not only soluble factor release by the MSC but also activation of the recipient's secretome. These two effects of MSC varied across target tissues and damaged-cell types. In conclusion, our work provides new insights into the regenerative properties of MSC and supports the ability of MSC from a single source to repair multiple types of damage, such as those seen after RP, in the same individual.